?-Synucleinopathies are neurodegenerative diseases characterized by intracellular inclusions of ?-synuclein (?- syn) aggregates and they include conditions such as Parkinson?s Disease (PD) and Dementia with Lewy Bodies (DLB). A prevailing view is that disease-associated factors such as aging compromise the ability of neurons to efficiently clear abnormally folded proteins which leads to the formation of intracellular aggregates and neurodegeneration. While enhancing the clearance of misfolded ?-syn is a potential therapeutic strategy for PD, current methods to activate cellular mechanisms for protein degradation rely mostly on pharmacological inducers or conventional gene delivery interventions. A translational roadblock in these approaches is the lack of control over dosage, precise time of intervention, and undesirable effects associated with the broad and sustained modulation of cellular degradation pathways. To address these therapeutic needs, we propose to develop a responsive gene therapy for the self-sufficient delivery of a neuroprotective therapy targeting the clearance of misfolded ?-syn species. In a cellular model of ?-syn seeded aggregation, we will demonstrate that our gene therapy approach can detect biological responses associated with the accumulation of ?-syn (Aim 1) and respond by modulating protein degradation pathways accordingly (Aim 2). We expect the outcomes of this project to enable a strategy where a therapy is produced as needed by the affected brain regions, opening the possibility to intervene at an early stage for the treatment of otherwise intractable neurodegenerative conditions such as PD. This project has the potential to be transformative as it introduces a modular platform technology with translational potential for other neurological targets linked to the neurotoxic behavior of misfolded proteins (e.g. amyloid-?, tau).